title: High expression of midkine in the airways of patients with cystic fibrosis.
abstract: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in impaired host defense during cystic fibrosis (CF), where Pseudomonas aeruginosa becomes a key pathogen. We investigated the expression pattern of the antibacterial growth factor midkine (MK) in CF and the possible interference with its activity by the altered airway microenvironment. High MK expression was found in CF lung tissue compared with control samples, involving epithelia of the large and small airways, alveoli, and cells of the submucosa (i.e., neutrophils and mast cells). In CF sputum, MK was present at 100-fold higher levels, but was also subject to increased degradation, compared with MK in sputum from healthy control subjects. MK exerted a bactericidal effect on P. aeruginosa, but increasing salt concentrations and low pH impaired this activity. Molecular modeling suggested that the effects of salt and pH were attributable to electrostatic screening and a charge-neutralization of the membrane, respectively. Both the neutrophil elastase and elastase of P. aeruginosa cleaved MK to smaller fragments, resulting in impaired bactericidal activity. Thus, MK is highly expressed in CF, but its bactericidal properties may be impaired by the altered microenvironment, as reflected by the in vitro conditions used in this study.
authors.affiliation: 1 Section of Respiratory Medicine and Allergology, and.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Nordin
authors.forename: Sandra
authors.initials: S
authors.lastname: Jovic
authors.forename: Anil
authors.initials: A
authors.lastname: Kurut
authors.forename: Cecilia
authors.initials: C
authors.lastname: Andersson
authors.forename: Anele
authors.initials: A
authors.lastname: Gela
authors.forename: Anders
authors.initials: A
authors.lastname: Bjartell
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Anders I
authors.initials: AI
authors.lastname: Olin
authors.forename: Mikael
authors.initials: M
authors.lastname: Lund
authors.forename: Arne
authors.initials: A
authors.lastname: Egesten
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000378:metabolism; D016022:Case-Control Studies; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008168:Lung / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000078792:Midkine; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000201:enzymology / Q000472:pathogenicity; D012492:Salts; D013183:Sputum / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; C066254:MDK protein, human; D009414:Nerve Growth Factors; D012492:Salts; D000078792:Midkine; D010196:Pancreatic Elastase